Summary Clonal hematopoiesis (CH) is a age-related and highly prevalent condition in the elderly that arises from somatic mutations in blood cells. CH increases in frequency with aging and is present in >10% of people aged >70 in the general population. Recent studies have identified CH as a major risk factor for coronary heart disease and ischemic stroke (CVD). Loss of function mutations of TET2 and JAK2V617F (JAK2VF), a gain of function mutation, are two common somatic mutations in CH. Using animal models, selective ablation of Tet2 gene or selective expression of JAK2VF in blood cells increases atherosclerosis, demonstrating the causality of CH-driving mutations in increased risk of CVD. Mechanistically, increased inflammation caused by Tet2-/- or Jak2VF contributes to atherosclerosis. Blood vascular integrity deficit also appears to promotes atherosclerosis in these animal models. Alzheimer?s disease (AD) is the most common type of late-life dementia. Among the risk factors, aging is the greatest. The mechanism linking aging and AD is still incompletely understood. Neuroinflammation and vascular disease are prominent contributors to AD. Dysregulated immunity is a common feature in AD. In addition to microglia, a major cell type that is involved in immunity and AD pathogenesis, blood derived immune cells could modulate AD pathogenesis as well. While both CH and AD are age-related and prevalent in the elderly, whether CH has a causal role in AD has not been assessed. The fact that atherosclerosis and AD share some common features and mechanisms and AD and CH related pathogenesis involve a battery of similar risk factors strongly suggests a causal link between CH and AD. We propose to assess the causality of CH in AD, using animal models. We will introduce bone marrow cells from Tet2-/- or Jak2VF mice into irradiated AD mouse models. Tet2-/- or Jak2VF will be expressed selectively in bone marrow derived blood cells in the recipient mice. Tet2-/- or Jak2VF expression is expected to exacerbate AD. This will be assessed by mouse behavior studies and pathological analysis of the brain tissues. We expect more pronounced learning and memory deficit in mice expressing Tet2-/- or Jak2VF, in association with exacerbated neuroinflammation and amyloid ? and tau related pathology. Once confirmed, we will carry out additional mechanistic studies to understand the underlying mechanism, including the potential role of macrophage inflammasome activation or neutrophil extracellular trap formation. Brain vascular integrity and function will be assessed as well. We believe that these proposed studies will help to define the potential adverse impact of CH on AD pathogenesis and progression. The mechanistic studies also have the potential to aid our understanding of the underlying mechanism and provide novel opportunities for development of novel therapeutic approaches.